Specific Ablation of Jak2 from CD11c+ Cells Attenuates Salt‐Sensitive Hypertension through an ENaC‐Dependent Mechanism

Abstract

Salt‐sensitivity of blood pressure affects 50% of hypertensive and 25% of normotensive individuals and is an independent predictor of death due to cardiovascular disease. We recently found that gamma and alpha subunits of the epithelial sodium channel (ENaCαγ) on dendritic cells mediate NADPH oxidase‐dependent formation of immunogenic isolevuglandin (IsoLG)‐protein adducts leading to inflammation and salt‐sensitive hypertension. We hypothesized that expression of Jak2 specifically in antigen presenting myeloid cells contributes to salt‐sensitive hypertension in an ENaC dependent mechanism. Profiling whole transcriptome using RNA‐Seq and analyzing the gene differential expression patterns in human monocytes reveals that high salt treatment upregulates genes of the Jak/STAT pathway, and the downstream regulators suppressor of cytokine signaling (SOCS) genes. Male and female mice lacking Jak2 in CD11c+ cells developed blunted hypertension (123.8±4.7) during the high salt feeding phase of the N‐Nitro‐L‐arginine methyl ester hydrochloride (L‐NAME)/high salt model of salt‐sensitive hypertension compared to the wildtype littermate controls (140.5±6.5). These mice also exhibited less infiltration of monocyte/macrophages in their kidneys and less volume retention in response to high salt‐feeding when compared to the wildtype littermate controls. We also found that deletion of Jak2 in dendritic cells reduced the salt‐induced expression of ENaCγ, and serum/glucocorticoid regulated kinase 1 (SGK1) in CD11c+ cells. Following high salt feeding, mice lacking Jak2 in DCs exhibited less renal infiltration of effector memory T cells (TEM), less aortic infiltration of CD11c+ cells with less expression of CD86, and less production of IsoLGs and IL1‐beta. These results indicate that dendritic cell Jak2 plays an important role in salt‐sensitive hypertension through an ENaC‐dependent mechanism.